ANORO

Dosage Forms And Strengths

Inhalation Powder. Disposable light grey and red plastic inhaler containing 2 foil blister strips of powder intended for oral inhalation only. One strip contains umeclidinium (62.5 mcg per blister), and the other strip contains vilanterol (25 mcg per blister).

Storage And Handling

ANORO ELLIPTA is supplied as a disposable light grey and red plastic inhaler containing 2 foil strips, each with 30 blisters (or 7 blisters for the institutional pack. One strip contains umeclidinium (62.5 mcg per blister), and the other strip contains vilanterol (25 mcg per blister). A blister from each strip is used to create 1 dose. The inhaler is packaged in a moisture-protective foil tray with a desiccant and a peelable lid in the following packs:

NDC 0173-0869-10 30 inhalations (60 blisters)
NDC 0173-0869-06 7 inhalations (14 blisters), institutional pack

Store at room temperature between 68°F and 77°F (20°C and 25°C); excursions permitted from 59°F to 86°F (15°C to 30°C). Store in a dry place away from direct heat or sunlight. Keep out of reach of children.

ANORO ELLIPTA should be stored inside the unopened moisture-protective foil tray and only removed from the tray immediately before initial use. Discard ANORO ELLIPTA 6 weeks after opening the foil tray or when the counter reads “0” (after all blisters have been used), whichever comes first. The inhaler is not reusable. Do not attempt to take the inhaler apart.

GlaxoSmithKline, Research Triangle Park, NC 27709. Revised: February 2016

ANORO ELLIPTA is a combination anticholinergic/long-acting beta₂-adrenergic agonist (anticholinergic/LABA) indicated for the long-term, once-daily, maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema.

Important Limitations Of Use

ANORO ELLIPTA is NOT indicated for the relief of acute bronchospasm or for the treatment of asthma.

ANORO ELLIPTA (umeclidinium/vilanterol 62.5 mcg/25 mcg) should be administered as 1 inhalation once daily by the orally inhaled route only.

ANORO ELLIPTA should be used at the same time every day. Do not use ANORO ELLIPTA more than 1 time every 24 hours.

No dosage adjustment is required for geriatric patients, patients with renal impairment, or patients with moderate hepatic impairment.

The use of ANORO ELLIPTA is contraindicated in patients with severe hypersensitivity to milk proteins or who have demonstrated hypersensitivity to umeclidinium, vilanterol, or any of the excipients.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Asthma-Related Death

Data from a large placebo-controlled trial in subjects with asthma showed that LABA may increase the risk of asthma-related death. Data are not available to determine whether the rate of death in patients with COPD is increased by LABA.

A 28-week, placebo-controlled, US trial comparing the safety of another LABA (salmeterol) with placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in subjects receiving salmeterol (13/13,176 in subjects treated with salmeterol vs. 3/13,179 in subjects treated with placebo; relative risk: 4.37 [95% CI: 1.25, 15.34]). The increased risk of asthma-related death is considered a class effect of LABA, including vilanterol, one of the active ingredients in ANORO ELLIPTA.

No trial adequate to determine whether the rate of asthma-related death is increased in subjects treated with ANORO ELLIPTA has been conducted. The safety and efficacy of ANORO ELLIPTA in patients with asthma have not been established. ANORO ELLIPTA is not indicated for the treatment of asthma.

Deterioration Of Disease and Acute Episodes

ANORO ELLIPTA should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of COPD. ANORO ELLIPTA has not been studied in subjects with acutely deteriorating COPD. The initiation of ANORO ELLIPTA in this setting is not appropriate.

ANORO ELLIPTA should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. ANORO ELLIPTA has not been studied in the relief of acute symptoms and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled, short-acting beta2-agonist.

When beginning treatment with ANORO ELLIPTA, patients who have been taking oral or inhaled, short-acting beta2-agonists on a regular basis (e.g., 4 times a day) should be instructed to discontinue the regular use of these drugs and to use them only for symptomatic relief of acute respiratory symptoms. When prescribing ANORO ELLIPTA, the healthcare provider should also prescribe an inhaled, short-acting beta2-agonist and instruct the patient on how it should be used. Increasing inhaled, short-acting beta2-agonist use is a signal of deteriorating disease for which prompt medical attention is indicated.

COPD may deteriorate acutely over a period of hours or chronically over several days or longer. If ANORO ELLIPTA no longer controls symptoms of bronchoconstriction; the patient's inhaled, short-acting beta2-agonist becomes less effective; or the patient needs more short-acting beta2-agonist than usual, these may be markers of deterioration of disease. In this setting a reevaluation of the patient and the COPD treatment regimen should be undertaken at once.

Increasing the daily dose of ANORO ELLIPTA beyond the recommended dose is not appropriate in this situation.

Excessive Use Of ANORO ELLIPTA And Use with Other Long-acting Beta2-agonists

ANORO ELLIPTA should not be used more often than recommended, at higher doses than recommended, or in conjunction with other medicines containing LABA, as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Patients using ANORO ELLIPTA should not use another medicine containing a LABA (e.g., salmeterol, formoterol fumarate, arformoterol tartrate, indacaterol) for any reason.

Drug Interactions With Strong Cytochrome P450 3A4 Inhibitors

Caution should be exercised when considering the coadministration of ANORO ELLIPTA with long-term ketoconazole and other known strong cytochrome P450 3A4 (CYP3A4) inhibitors (e.g., ritonavir, clarithromycin, conivaptan, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, saquinavir, telithromycin, troleandomycin, voriconazole) because increased cardiovascular adverse effects may occur.

Paradoxical Bronchospasm

As with other inhaled medicines, ANORO ELLIPTA can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with ANORO ELLIPTA, it should be treated immediately with an inhaled, short-acting bronchodilator; ANORO ELLIPTA should be discontinued immediately; and alternative therapy should be instituted.

Hypersensitivity Reactions

Hypersensitivity reactions such as anaphylaxis, angioedema, rash, and urticaria may occur after administration of ANORO ELLIPTA. Discontinue ANORO ELLIPTA if such reactions occur. There have been reports of anaphylactic reactions in patients with severe milk protein allergy after inhalation of other powder products containing lactose; therefore, patients with severe milk protein allergy should not use ANORO ELLIPTA.

Cardiovascular Effects

Vilanterol, like other beta2-agonists, can produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, systolic or diastolic blood pressure, or symptoms. If such effects occur, ANORO ELLIPTA may need to be discontinued. In addition, beta-agonists have been reported to produce electrocardiographic changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression, although the clinical significance of these findings is unknown.

Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs.

Therefore, ANORO ELLIPTA should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

Coexisting Conditions

ANORO ELLIPTA, like all medicines containing sympathomimetic amines, should be used with caution in patients with convulsive disorders or thyrotoxicosis and in those who are unusually responsive to sympathomimetic amines. Doses of the related beta2-adrenoceptor agonist albuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis.

Worsening Of Narrow-Angle Glaucoma

ANORO ELLIPTA should be used with caution in patients with narrow-angle glaucoma. Prescribers and patients should be alert for signs and symptoms of acute narrow-angle glaucoma (e.g., eye pain or discomfort, blurred vision, visual halos or colored images in association with red eyes from conjunctival congestion and corneal edema). Instruct patients to consult a healthcare provider immediately if any of these signs or symptoms develops.

Worsening Of Urinary Retention

ANORO ELLIPTA should be used with caution in patients with urinary retention. Prescribers and patients should be alert for signs and symptoms of urinary retention (e.g., difficulty passing urine, painful urination), especially in patients with prostatic hyperplasia or bladder-neck obstruction. Instruct patients to consult a healthcare provider immediately if any of these signs or symptoms develops.

Hypokalemia And Hyperglycemia

Beta-adrenergic agonist medicines may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects. The decrease in serum potassium is usually transient, not requiring supplementation. Beta-agonist medicines may produce transient hyperglycemia in some patients. In 4 clinical trials of 6-month duration evaluating ANORO ELLIPTA in subjects with COPD, there was no evidence of a treatment effect on serum glucose or potassium.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).

Asthma-Related Death

Inform patients that LABA, such as vilanterol, one of the active ingredients in ANORO ELLIPTA, increase the risk of asthma-related death. ANORO ELLIPTA is not indicated for the treatment of asthma.

Not For Acute Symptoms

Inform patients that ANORO ELLIPTA is not meant to relieve acute symptoms of COPD and extra doses should not be used for that purpose. Advise patients to treat acute symptoms with an inhaled, short-acting beta2-agonist such as albuterol. Provide patients with such medicine and instruct them in how it should be used.

Instruct patients to seek medical attention immediately if they experience any of the following:

• Decreasing effectiveness of inhaled, short-acting beta2-agonists
• Need for more inhalations than usual of inhaled, short-acting beta2-agonists
• Significant decrease in lung function as outlined by the physician

Tell patients they should not stop therapy with ANORO ELLIPTA without healthcare provider guidance since symptoms may recur after discontinuation.

Do Not Use Additional Long-acting Beta2-agonists

Instruct patients not to use other medicines containing a LABA. Patients should not use more than the recommended once-daily dose of ANORO ELLIPTA.

Instruct patients who have been taking inhaled, short-acting beta2-agonists on a regular basis to discontinue the regular use of these products and use them only for the symptomatic relief of acute symptoms.

Paradoxical Bronchospasm

As with other inhaled medicines, ANORO ELLIPTA can cause paradoxical bronchospasm. If paradoxical bronchospasm occurs, instruct patients to discontinue ANORO ELLIPTA and contact their healthcare provider right away.

Risks Associated With Beta-agonist Therapy

Inform patients of adverse effects associated with beta2-agonists, such as palpitations, chest pain, rapid heart rate, tremor, or nervousness.

Worsening Of Narrow-Angle Glaucoma

Instruct patients to be alert for signs and symptoms of acute narrow-angle glaucoma (e.g., eye pain or discomfort, blurred vision, visual halos or colored images in association with red eyes from conjunctival congestion and corneal edema). Instruct patients to consult a healthcare provider immediately if any of these signs or symptoms develops.

Worsening Of Urinary Retention

Instruct patients to be alert for signs and symptoms of urinary retention (e.g., difficulty passing urine, painful urination). Instruct patients to consult a healthcare provider immediately if any of these signs or symptoms develops.

ANORO and ELLIPTA are registered trademarks of the GSK group of companies. ANORO ELLIPTA was developed in collaboration with INNOVIVA.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

ANORO ELLIPTA

No studies of carcinogenicity, mutagenicity, or impairment of fertility were conducted with ANORO ELLIPTA; however, studies are available for the individual components, umeclidinium and vilanterol, as described below.

Umeclidinium

Umeclidinium produced no treatment-related increases in the incidence of tumors in 2-year inhalation studies in rats and mice at inhaled doses up to 137 and 295/200 mcg/kg/day (male/female), respectively (approximately 20 and 25/20 times the MRHDID in adults on an AUC basis, respectively).

Umeclidinium tested negative in the following genotoxicity assays: the in vitro Ames assay, in vitro mouse lymphoma assay, and in vivo rat bone marrow micronucleus assay.

No evidence of impairment of fertility was observed in male and female rats at subcutaneous doses up to 180 mcg/kg/day and inhaled doses up to 294 mcg/kg/day, respectively (approximately 100 and 50 times, respectively, the MRHDID in adults on an AUC basis).

Vilanterol

In a 2-year carcinogenicity study in mice, vilanterol caused a statistically significant increase in ovarian tubulostromal adenomas in females at an inhalation dose of 29,500 mcg/kg/day (approximately 7,800 times the MRHDID in adults on an AUC basis). No increase in tumors was seen at an inhalation dose of 615 mcg/kg/day (approximately 210 times the MRHDID in adults on an AUC basis).

In a 2-year carcinogenicity study in rats, vilanterol caused statistically significant increases in mesovarian leiomyomas in females and shortening of the latency of pituitary tumors at inhalation doses greater than or equal to 84.4 mcg/kg/day (greater than or equal to approximately 20 times the MRHDID in adults on an AUC basis). No tumors were seen at an inhalation dose of 10.5 mcg/kg/day (approximately 1 time the MRHDID in adults on an AUC basis).

These tumor findings in rodents are similar to those reported previously for other beta-adrenergic agonist drugs. The relevance of these findings to human use is unknown.

Vilanterol tested negative in the following genotoxicity assays: the in vitro Ames assay, in vivo rat bone marrow micronucleus assay, in vivo rat unscheduled DNA synthesis (UDS) assay, and in vitro Syrian hamster embryo (SHE) cell assay. Vilanterol tested equivocal in the in vitro mouse lymphoma assay.

No evidence of impairment of fertility was observed in reproductive studies conducted in male and female rats at inhaled vilanterol doses up to 31,500 and 37,100 mcg/kg/day, respectively (approximately 12,000 and 14,500 times, respectively, the MRHDID in adults on a mcg/m² basis).

Use In Specific Populations

Pregnancy

Teratogenic Effects

Pregnancy Category C. There are no adequate and well-controlled trials of ANORO ELLIPTA or its individual components, umeclidinium and vilanterol, in pregnant women. Because animal reproduction studies are not always predictive of human response, ANORO ELLIPTA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Women should be advised to contact their healthcare providers if they become pregnant while taking ANORO ELLIPTA.

Umeclidinium

There was no evidence of teratogenic effects in rats and rabbits at approximately 50 and 200 times, respectively, the MRHDID (maximum recommended human daily inhaled dose) in adults (on an AUC basis at maternal inhaled doses up to 278 mcg/kg/day in rats and at maternal subcutaneous doses up to 180 mcg/kg/day in rabbits).

Vilanterol

There were no teratogenic effects in rats and rabbits at approximately 13,000 and 70 times, respectively, the MRHDID in adults (on a mcg/m² basis at maternal inhaled doses up to 33,700 mcg/kg/day in rats and on an AUC basis at maternal inhaled doses up to 591 mcg/kg/day in rabbits). However, fetal skeletal variations were observed in rabbits at approximately 450 times the MRHDID in adults (on an AUC basis at maternal inhaled or subcutaneous doses of 5,740 or 300 mcg/kg/day, respectively). The skeletal variations included decreased or absent ossification in cervical vertebral centrum and metacarpals.

Nonteratogenic Effects

Umeclidinium

There were no effects on perinatal and postnatal developments in rats at approximately 80 times the MRHDID in adults (on an AUC basis at maternal subcutaneous doses up to 180 mcg/kg/day).

Vilanterol

There were no effects on perinatal and postnatal developments in rats at approximately 3,900 times the MRHDID in adults (on a mcg/m² basis at maternal oral doses up to 10,000 mcg/kg/day).

Labor And Delivery

There are no adequate and well-controlled human trials that have investigated the effects of ANORO ELLIPTA during labor and delivery.

Because beta-agonists may potentially interfere with uterine contractility, ANORO ELLIPTA should be used during labor only if the potential benefit justifies the potential risk.

Nursing Mothers

ANORO ELLIPTA

It is not known whether ANORO ELLIPTA is excreted in human breast milk. Because many drugs are excreted in human milk, caution should be exercised when ANORO ELLIPTA is administered to a nursing woman. Since there are no data from well-controlled human studies on the use of ANORO ELLIPTA by nursing mothers, based on the data for the individual components, a decision should be made whether to discontinue nursing or to discontinue ANORO ELLIPTA, taking into account the importance of ANORO ELLIPTA to the mother.

Umeclidinium

It is not known whether umeclidinium is excreted in human breast milk. However, administration to lactating rats at approximately 25 times the MRHDID in adults resulted in a quantifiable level of umeclidinium in 2 pups, which may indicate transfer of umeclidinium in milk.

Vilanterol

It is not known whether vilanterol is excreted in human breast milk. However, other beta2-agonists have been detected in human milk.

Pediatric Use

ANORO ELLIPTA is not indicated for use in children. The safety and efficacy in pediatric patients have not been established.

Geriatric Use

Based on available data, no adjustment of the dosage of ANORO ELLIPTA in geriatric patients is necessary, but greater sensitivity in some older individuals cannot be ruled out.

Clinical trials of ANORO ELLIPTA for COPD included 2,143 subjects aged 65 years and older and 478 subjects aged 75 years and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger subjects.

Hepatic Impairment

Patients with moderate hepatic impairment (Child-Pugh score of 7-9) showed no relevant increases in Cmax or AUC, nor did protein binding differ between subjects with moderate hepatic impairment and their healthy controls. Studies in subjects with severe hepatic impairment have not been performed.

Renal Impairment

There were no significant increases in either umeclidinium or vilanterol exposure in subjects with severe renal impairment (CrCl less than 30 mL/min) compared with healthy subjects. No dosage adjustment is required in patients with renal impairment.

When umeclidinium and vilanterol were administered in combination by the inhaled route, the pharmacokinetic parameters for each component were similar to those observed when each active substance was administered separately.

Inhibitors Of Cytochrome P450 3A4

Vilanterol is a substrate of CYP3A4. A double-blind, repeat-dose, 2-way crossover drug interaction trial was conducted in healthy subjects to investigate the pharmacokinetic and pharmacodynamic effects of vilanterol 25 mcg as an inhalation powder with ketoconazole 400 mg. The plasma concentrations of vilanterol were higher after single and repeated doses when coadministered with ketoconazole than with placebo (Figure 2). The increase in vilanterol exposure was not associated with an increase in beta-agonist-related systemic effects on heart rate or blood potassium.

Inhibitors Of P-glycoprotein Transporter

Umeclidinium and vilanterol are both substrates of P-gp. The effect of the moderate P-gp transporter inhibitor verapamil (240 mg once daily) on the steady-state pharmacokinetics of umeclidinium and vilanterol was assessed in healthy subjects. No effect on umeclidinium or vilanterol Cmax was observed; however, an approximately 1.4-fold increase in umeclidinium AUC was observed with no effect on vilanterol AUC (Figure 2).

Inhibitors Of Cytochrome P450 2D6

In vitro metabolism of umeclidinium is mediated primarily by CYP2D6. However, no clinically meaningful difference in systemic exposure to umeclidinium (500 mcg) (8 times the approved dose) was observed following repeat daily inhaled dosing in CYP2D6 normal (ultrarapid, extensive, and intermediate metabolizers) and poor metabolizer subjects (Figure 1).

Figure 2: Impact of Extrinsic Factors on the Pharmacokinetics (PK) of Umeclidinium (UMEC) and Vilanterol (VI)

Teratogenic Effects

Pregnancy Category C. There are no adequate and well-controlled trials of ANORO ELLIPTA or its individual components, umeclidinium and vilanterol, in pregnant women. Because animal reproduction studies are not always predictive of human response, ANORO ELLIPTA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Women should be advised to contact their healthcare providers if they become pregnant while taking ANORO ELLIPTA.

Umeclidinium

There was no evidence of teratogenic effects in rats and rabbits at approximately 50 and 200 times, respectively, the MRHDID (maximum recommended human daily inhaled dose) in adults (on an AUC basis at maternal inhaled doses up to 278 mcg/kg/day in rats and at maternal subcutaneous doses up to 180 mcg/kg/day in rabbits).

Vilanterol

There were no teratogenic effects in rats and rabbits at approximately 13,000 and 70 times, respectively, the MRHDID in adults (on a mcg/m² basis at maternal inhaled doses up to 33,700 mcg/kg/day in rats and on an AUC basis at maternal inhaled doses up to 591 mcg/kg/day in rabbits). However, fetal skeletal variations were observed in rabbits at approximately 450 times the MRHDID in adults (on an AUC basis at maternal inhaled or subcutaneous doses of 5,740 or 300 mcg/kg/day, respectively). The skeletal variations included decreased or absent ossification in cervical vertebral centrum and metacarpals.

Nonteratogenic Effects

Umeclidinium

There were no effects on perinatal and postnatal developments in rats at approximately 80 times the MRHDID in adults (on an AUC basis at maternal subcutaneous doses up to 180 mcg/kg/day).

Vilanterol

There were no effects on perinatal and postnatal developments in rats at approximately 3,900 times the MRHDID in adults (on a mcg/m² basis at maternal oral doses up to 10,000 mcg/kg/day).

LABA, such as vilanterol, one of the active ingredients in ANORO ELLIPTA, increase the risk of asthma-related death. ANORO ELLIPTA is not indicated for the treatment of asthma.

The following adverse reactions are described in greater detail in other sections:

• Paradoxical bronchospasm
• Cardiovascular effects
• Worsening of narrow-angle glaucoma
• Worsening of urinary retention

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The clinical program for ANORO ELLIPTA included 8,138 subjects with COPD in four 6-month lung function trials, one 12-month long-term safety study, and 9 other trials of shorter duration. A total of 1,124 subjects have received at least 1 dose of ANORO ELLIPTA (umeclidinium/vilanterol 62.5 mcg/25 mcg), and 1,330 subjects have received a higher dose of umeclidinium/vilanterol (125 mcg/25 mcg). The safety data described below are based on the four 6-month and the one 12-month trials. Adverse reactions observed in the other trials were similar to those observed in the confirmatory trials.

6-Month Trials

The incidence of adverse reactions associated with ANORO ELLIPTA in Table 1 is based on four 6-month trials: 2 placebo-controlled trials (Trials 1 and 2; n = 1,532 and n = 1,489, respectively) and 2 active-controlled trials (Trials 3 and 4; n = 843 and n = 869, respectively). Of the 4,733 subjects, 68% were male and 84% were white. They had a mean age of 63 years and an average smoking history of 45 pack-years, with 50% identified as current smokers. At screening, the mean postbronchodilator percent predicted forced expiratory volume in 1 second (FEV₁) was 48% (range: 13% to 76%), the mean postbronchodilator FEV₁/forced vital capacity (FVC) ratio was 0.47 (range: 0.13 to 0.78), and the mean percent reversibility was 14% (range: -45% to 109%).

Subjects received 1 dose once daily of the following: ANORO ELLIPTA, umeclidinium/vilanterol 125 mcg/25 mcg, umeclidinium 62.5 mcg, umeclidinium 125 mcg, vilanterol 25 mcg, active control, or placebo.

Table 1: Adverse Reactions with ANORO ELLIPTA with ≥1% Incidence and More Common than Placebo in Subjects with Chronic Obstructive Pulmonary Disease

Other adverse reactions with ANORO ELLIPTA observed with an incidence less than 1% but more common than placebo included the following: productive cough, dry mouth, dyspepsia, abdominal pain, gastroesophageal reflux disease, vomiting, musculoskeletal chest pain, chest discomfort, asthenia, atrial fibrillation, ventricular extrasystoles, supraventricular extrasystoles, myocardial infarction, pruritus, rash, and conjunctivitis.

12-Month Trial

In a long-term safety trial, 335 subjects were treated for up to 12 months with umeclidinium/vilanterol 125 mcg/25 mcg or placebo. The demographic and baseline characteristics of the long-term safety trial were similar to those of the placebo-controlled efficacy trials described above. Adverse reactions that occurred with a frequency of greater than or equal to 1% in the group receiving umeclidinium/vilanterol 125 mcg/25 mcg that exceeded that in placebo in this trial were: headache, back pain, sinusitis, cough, urinary tract infection, arthralgia, nausea, vertigo, abdominal pain, pleuritic pain, viral respiratory tract infection, toothache, and diabetes mellitus.

Postmarketing Experience

In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during postapproval use of ANORO ELLIPTA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, or causal connection to ANORO ELLIPTA or a combination of these factors.

Cardiac Disorders

Palpitations.

Eye Disorders

Blurred vision, glaucoma, increased intraocular pressure.

Immune System Disorders

Hypersensitivity reactions, including anaphylaxis, angioedema, and urticaria.

Nervous System Disorders

Dysgeusia, tremor.

Psychiatric Disorders

Anxiety.

Renal and Urinary Disorders

Dysuria, urinary retention.

Respiratory, Thoracic, and Mediastinal Disorders

Dysphonia, paradoxical bronchospasm.

No case of overdose has been reported with ANORO ELLIPTA.

ANORO ELLIPTA contains both umeclidinium and vilanterol; therefore, the risks associated with overdosage for the individual components described below apply to ANORO ELLIPTA. Treatment of overdosage consists of discontinuation of ANORO ELLIPTA together with institution of appropriate symptomatic and/or supportive therapy. The judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medicine can produce bronchospasm. Cardiac monitoring is recommended in cases of overdosage.

Umeclidinium

High doses of umeclidinium may lead to anticholinergic signs and symptoms. However, there were no systemic anticholinergic adverse effects following a once-daily inhaled dose of up to 1,000 mcg umeclidinium (16 times the maximum recommended daily dose) for 14 days in subjects with COPD.

Vilanterol

The expected signs and symptoms with overdosage of vilanterol are those of excessive beta-adrenergic stimulation and/or occurrence or exaggeration of any of the signs and symptoms of beta-adrenergic stimulation (e.g., angina, hypertension or hypotension, tachycardia with rates up to 200 beats/min, arrhythmias, nervousness, headache, tremor, seizures, muscle cramps, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, insomnia, hyperglycemia, hypokalemia, metabolic acidosis). As with all inhaled sympathomimetic medicines, cardiac arrest and even death may be associated with an overdose of vilanterol.

Cardiovascular Effects

Healthy Subjects

QTc interval prolongation was studied in a double-blind, multiple-dose, placebo- and positive-controlled crossover trial in 86 healthy subjects. The maximum mean (95% upper confidence bound) difference in QTcF from placebo after baseline correction was 4.6 (7.1) milliseconds and 8.2 (10.7) milliseconds for umeclidinium/vilanterol 125 mcg/25 mcg and umeclidinium/vilanterol 500 mcg/100 mcg (8/4 times the recommended dosage), respectively.

A dose-dependent increase in heart rate was also observed. The maximum mean (95% upper confidence bound) difference in heart rate from placebo after baseline correction was 8.8 (10.5) beats/min and 20.5 (22.3) beats/min seen 10 minutes after dosing for umeclidinium/vilanterol 125 mcg/25 mcg and umeclidinium/vilanterol 500 mcg/100 mcg, respectively.

Chronic Obstructive Pulmonary Disease

The effect of ANORO ELLIPTA on cardiac rhythm in subjects diagnosed with COPD was assessed using 24-hour Holter monitoring in 6- and 12-month trials: 53 subjects received ANORO ELLIPTA, 281 subjects received umeclidinium/vilanterol 125 mcg/25 mcg, and 182 subjects received placebo. No clinically meaningful effects on cardiac rhythm were observed.

Linear pharmacokinetics was observed for umeclidinium (62.5 to 500 mcg) and vilanterol (25 to 100 mcg).

Absorption

Umeclidinium

Umeclidinium plasma levels may not predict therapeutic effect. Following inhaled administration of umeclidinium in healthy subjects, Cmax occurred at 5 to 15 minutes. Umeclidinium is mostly absorbed from the lung after inhaled doses with minimum contribution from oral absorption. Following repeat dosing of inhaled ANORO ELLIPTA, steady state was achieved within 14 days with up to 1.8-fold accumulation.

Vilanterol

Vilanterol plasma levels may not predict therapeutic effect. Following inhaled administration of vilanterol in healthy subjects, Cmax occurred at 5 to 15 minutes. Vilanterol is mostly absorbed from the lung after inhaled doses with negligible contribution from oral absorption. Following repeat dosing of inhaled ANORO ELLIPTA, steady state was achieved within 14 days with up to 1.7-fold accumulation.

Distribution

Umeclidinium

Following intravenous administration to healthy subjects, the mean volume of distribution was 86 L. In vitro plasma protein binding in human plasma was on average 89%.

Vilanterol

Following intravenous administration to healthy subjects, the mean volume of distribution at steady state was 165 L. In vitro plasma protein binding in human plasma was on average 94%.

Metabolism

Umeclidinium

In vitro data showed that umeclidinium is primarily metabolized by the enzyme cytochrome P450 2D6 (CYP2D6) and is a substrate for the P-glycoprotein (P-gp) transporter. The primary metabolic routes for umeclidinium are oxidative (hydroxylation, O-dealkylation) followed by conjugation (e.g., glucuronidation), resulting in a range of metabolites with either reduced pharmacological activity or for which the pharmacological activity has not been established. Systemic exposure to the metabolites is low.

Vilanterol

In vitro data showed that vilanterol is metabolized principally by CYP3A4 and is a substrate for the P-gp transporter. Vilanterol is metabolized to a range of metabolites with significantly reduced β1- and β2-agonist activity.

Elimination

Umeclidinium

Following intravenous dosing with radiolabeled umeclidinium, mass balance showed 58% of the radiolabel in the feces and 22% in the urine. The excretion of the drug-related material in the feces following intravenous dosing indicated elimination in the bile. Following oral dosing to healthy male subjects, radiolabel recovered in feces was 92% of the total dose and that in urine was less than 1% of the total dose, suggesting negligible oral absorption. The effective half-life after once-daily dosing is 11 hours.

Vilanterol

Following oral administration of radiolabeled vilanterol, mass balance showed 70% of the radiolabel in the urine and 30% in the feces. The effective half-life for vilanterol, as determined from inhalation administration of multiple doses, is 11 hours.